I. Problem/Condition.

Urine studies can provide a wide variety of information, including the etiology of acute kidney injury (AKI) and the presence of a urinary tract infection (UTI). It is relatively inexpensive and can even be performed by the testing physician. Specific urine tests that are useful in the inpatient setting include:

Urine microscopy, in which the urine is examined for the presence of cells or cellular casts that can provide information about the presence of a UTI or possible causes of AKI

Urine culture, which can confirm the presence of a UTI and identify the causative bacteria

Urine electrolyte testing, which can provide useful information about a patient’s intravascular volume status and possible causes of AKI or serum electrolyte abnormalities

Urine protein, which is usually used to assess for glomerular disease

Two common scenarios in which urine studies are useful are AKI and UTI, described below.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The differential diagnosis of AKI

The first step in the work-up of AKI is developing a differential diagnosis. A study by Nash et al. examining the most common causes of hospital-acquired AKI found the top three to be decreased renal perfusion ("prerenal"), medications, and contrast-induced nephropathy. These three causes account for approximately two-thirds of cases of AKI that occur in the hospital, and thus urine testing that is able to distinguish among these will provide the highest diagnostic yield. In contrast, quantifying the degree of proteinuria, which is helpful in diagnosing glomerular disease, is unlikely to be as useful since glomerulonephritis is rarely a cause of hospital-acquired AKI.

The differential diagnosis of UTI

When patients present with urinary symptoms such as dysuria and urinary frequency, a UTI is often the top diagnostic consideration. Systemic symptoms such as fever and leukocytosis may accompany urinary symptoms if the infection is severe or ascending. Other conditions in the differential diagnosis include vaginal infections, such as Trichomonas, and sexually transmitted infections, such as Neisseria gonorrhoeae. Urine dipstick testing can help suggest the diagnosis of a UTI, while urine culture can confirm it.

B. Describe a diagnostic approach/method to the patient with this problem.

Not applicable.

1. Historical information important in the diagnosis of this problem.

Not applicable.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Not applicable.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

The Use of Urine Tests with AKI

Urine tests in the setting of AKI can help distinguish between AKI that is due to renal hypoperfusion (commonly called prerenal AKI), and AKI that is due to acute tubular necrosis, such as from an ischemic insult or nephrotoxic medication (commonly called intrarenal AKI). This can help determine if the patient’s AKI should be treated with intravascular volume repletion versus removing the insulting agent. Of note, sustained renal hypoperfusion can lead to ATN.

Urine Sodium

The kidney responds to hypoperfusion by attempting to restore intravascular volume by becoming sodium avid. The kidney can be hypoperfused when the patient is hypovolemic, as with severe diarrhea. Renal hypoperfusion can also result from states of decreased effective circulating volume, even when the patient is total-body-fluid overloaded, as may occur with decompensated congestive heart failure or cirrhosis.

When the kidney is sodium avid due to hypoperfusion, the urine sodium will be low (below 20 mEq/L). In ATN, the renal tubule cells are damaged and incapable of aggressively reabsorbing sodium, resulting in a higher urine sodium (above 40 mEq/L). Urine sodium values between 20 and 40 mEq/L are considered indeterminate.

Fractional Excretion of Sodium (FENa)

The fractional excretion of sodium (FENa) has the advantage of being less reflective of water-handling than the urine sodium is, and its use is preferred over the urine sodium in acute injury in a patient with chronic kidney disease. The FENa has the greatest utility when the patient is oliguric. The FENa (as a %) is calculated as:

The FENa is used in a manner analogous to the urine sodium - a FENa less than 1% suggests kidney hypoperfusion (prerenal injury) while a FENa higher than 2% suggests inability to reabsorb sodium, as in ATN (intrarenal injury).

Some caveats apply when using the FENa. Because of the large amount of sodium that is filtered with a normal glomerular filtration rate, a FENa less than 1% may be normal in patients without AKI, depending on sodium intake. Moreover, certain types of ATN—including contrast-induced nephropathy, glomerulonephritis, and heme pigment-induced AKI—may have a low FENa. This underscores the importance of clinical correlation when interpreting diagnostic studies.

Diuretics and the Fractional Excretion of Urea (FEurea)

The administration of diuretics can complicate the interpretation of the FENa. The sodium avidity of a hypoperfused kidney may be overcome by the natriuretic effect of diuretics. Therefore, a FENa higher than 2% in a patient on diuretics is unreliable as it could be a result of diuretics rather than ATN. However, a FENa that is less than 1% despite the patient being on diuretics does suggest renal hypoperfusion.

The fractional excretion of urea (FEurea) has been suggested as an alternative urine index that is supposedly less affected by diuretics than the FENa. The FEurea is calculated in the same way as the FENa, except that urine urea is used in place of urine sodium, and the serum urea (also known as the blood urea nitrogen) is used in place of the serum sodium. A FEurea less than 35% suggests hypoperfusion (similar to the FENa <1%), and an FEurea above 50% suggests ATN (similar to a FENa >2%). However, the limited literature on the utility of the FEurea versus the FENa is inconsistent, and it is unclear whether the FEurea is truly superior to the FENa in the setting of diuretics. Calculation of both the FENa and FEurea in patients on diuretics should be considered to maximize the data available for clinical decision making.

Table 1 summarizes how urine electrolytes can be used to assist in determining the etiology of AKI.

Table 1.

Urine Findings in AKI

Etiology of AKI

Urine Na

FENa

FEurea

Proteinuria

Prerenal

< 20 mEq/L

< 1%

< 35%

minimal

Intrarenal: ATN

> 40 mEq/L

>2%

> 50%

minimal

Intrarenal: GN

< 20 mEq/L

<1%

< 35%

> 250 mg/24 hr

The Use of Urine Tests in Diagnosing a UTI

The initial test used in evaluating for UTI is usually a urine dipstick analysis, focusing on the leukocytes esterase and nitrite portion of the dipstick. A positive result in either leukocyte esterase or nitrite (or both) is considered a positive urine dipstick test for UTI. Using either leukocyte esterase or nitrite (or both) to denote a positive dipstick test for a UTI yields a sensitivity of 75 percent and a specificity of 82 percent. If there is high clinical suspicion of UTI, a negative urine dipstick does not necessarily exclude the diagnosis.

Urine dipstick testing for UTI has several limitations. Some clinically important bacteria, such as Pseudomonas, do not produce nitrites (from nitrates), and thus they will not turn the nitrite portion of the dipstick positive. In addition, urine dipsticks that are exposed to air for a prolonged period can have false negative readings.

In the outpatient setting, symptoms consistent with a lower UTI and a positive dipstick warrant treatment without requiring a urine culture. In the inpatient setting, however, a urine culture should always be obtained (ideally prior to administering antibiotics), since the likelihood of a resistant organism is higher. Empiric treatment can be started based on the clinical history and urine dipstick results prior to culture results. Of note, patients can have a urinalysis suggestive of infection with a negative culture, a phenomenon known as sterile pyuria. The etiology of sterile pyuria includes interstitial nephritis, renal tuberculosis, and nephrolithiasis, as well as sexually transmitted bacterial infections and non-bacterial infections.

The conventional standard used by clinical microbiology labs to define a positive urine culture is at least 105 cfu/ml of urine. This threshold maximizes specificity but does so at the expense of sensitivity, thus some authors advocate using lower bacterial counts to constitute a positive culture. The presence of three or more types of bacteria in a urine culture suggests a contaminated specimen. The timing of the urine culture relative to the administration of antibiotics should be considered; even a single dose of antibiotics can lead to a negative urine culture in a patient with a UTI, as the antibiotics may be excreted in the urine and present in the culture.

Urinary Casts

Casts in the urine, formed when cellular elements in the urine embed in Tamm-Horsfall glycoproteins and take the shape of the collecting tubules, can provide important clinical information. The presence of casts can suggest a diagnosis, but the absence of casts cannot rule one out because casts may degrade, depending on how the urine is handled. One should also consider the experience of the person who is examining the urine sample for casts; when identifying casts is critical to making a diagnosis, it is advisable to ask a nephrologist to examine the urine rather than solely rely on the clinical laboratory.

Table 2 lists the types of casts and their clinical significance.

Table 2.

Significance of Urinary Casts

Cast Type

Associated Condition

red blood cell

glomerulonephritis

white blood cell

pyelonephritis; also interstitial nephritis

renal tubular epithelial cell

ATN

granular

represents degraded cellular elements; non-specific

hyaline

can be normal; non-specific

Urine Eosinophils

Urine eosinophils are commonly thought to be associated with acute interstitial nephritis (AIN), which is kidney injury characterized by an inflammatory infiltrate that is often due to drugs or autoimmune disease. Although older data supported this belief, more recent studies have shown urine eosinophils to be unreliable in diagnosing AIN as it lacks sensitivity and specificity. Renal biopsy remains the gold standard in diagnosing AIN.

Proteinuria

Measuring protein in the urine is useful in diagnosing glomerular disease. The urine dipstick, although often referred to as measuring proteinuria, actually primarily measures albuminuria. This is an important distinction because in some renal diseases, such as myeloma kidney, the main protein spilled in the urine is not albumin and thus urine dipstick may miss this diagnosis. The primary protein spilled in the urine in myeloma kidney is a monoclonal light chain (Bence-Jones protein). This can be measured with either a spot protein-to-creatinine ratio or a 24-hour urine collection for protein.

Most urine dipsticks will turn positive for protein at an albumin level of approximately 20-30 mg/dL. Urine dipsticks are only semi-quantitative, since the degree of proteinuria they register will be affected by the concentration of the urine specimen being tested.

A random ("spot") urine protein-to-creatinine ratio is a useful method to quantify the amount of proteinuria. The ratio of protein (in mg/dL) to creatinine (in mg/dL) in a random urine sample gives a good estimate (r=0.97) of the amount of protein excreted in the urine in grams/1.73M2 of body surface area per 24 hours. A random urine can be used to obtain either the protein-to-creatinine ratio or albumin-to-creatinine ratio, depending on the clinical need.

The advantage of using a random urine to measure the protein-to-creatinine ratio is that this measurement will detect the non-albumin proteins in the urine, which are generally not detected via dipstick measurement. However, in some cases measuring the albumin-to-creatinine ratio is more appropriate, such as when following the progression of diabetic nephropathy.

The third way to measure proteinuria (in addition to dipstick measurement and protein-to-creatinine ratio) is by 24-hour urine collection. This method has a number of disadvantages, including being cumbersome to collect and the possibility of an incomplete urine collection (leading to an underestimation of proteinuria). This method may have a limited role in providing serial estimations of proteinuria in the outpatient setting in order to assess response to therapy (such as in a glomerulonephritis patient receiving immunosuppression). The National Kidney Foundation’s guideline recommends the urine albumin-to-creatinine ratio as the preferred method for measuring albuminuria.

Clinically, proteinuria is most important as a sign of glomerular disease (when the proteinuria is albuminuria) or myeloma kidney (when the proteinuria is light chains). The presence of proteinuria of at least 3.5 grams/24 hours constitutes nephrotic-range proteinuria. When nephrotic-range proteinuria is accompanied by peripheral edema, hyperlipidemia, and hypoalbuminemia (<2.5-3 g/dL), full-fledged nephrotic syndrome is present. Proteinuria has extra-renal manifestations, including an increased risk of venous thromboembolism.

Hematuria

Red blood cells’ (RBCs) will turn the heme portion of the urine dipstick positive at a threshold of 1-5 RBCs per high power field. In addition to RBCs in the urine, myoglobin (as with rhabdomyolysis) or hemoglobin (as with hemolysis) can lead to a heme-positive urine dipstick. A urine dipstick that is positive for heme combined with a urine microscopy examination absent of RBCs raises the possibility of either rhabdomyolysis or hemolysis. Centrifugation of the urine can be helpful in these instance as the sediment will be normal and the supernatant will have a reddish hue (due to the presence of the myoglobin or hemoglobin in the supernatant) with myoglobinuria or hemoglobinuria, while centrifugation will result in a red sediment (because of the pellet of RBCs) and a light yellow supernatant with hematuria.

If true hematuria is confirmed by urine microscopy, it is useful to consider whether it is glomerular in origin or is from elsewhere in the urinary tract. The presence of RBC casts or dysmorphic RBCs, which suggests a glomerular origin, should prompt a workup for glomerulonephritis or a vasculitis affecting the kidney. When the hematuria appears to be non-glomerular in origin, elements of the workup can include upper tract imaging (such as CT urography), urine cytology, and cystoscopy.

The exact workup depends on the patient’s risk factors and the clinical context. Among adults, the most common causes of hematuria are UTIs, transitional cell cancer, renal cancer, benign prostatic hypertrophy, and nephrolithiasis. In a significant proportion of patients with hematuria (upwards of 40% in some studies), no source for the hematuria is identified.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Not applicable.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Urine Osmolality

Perhaps the most overused urine test is urine osmolality. Many clinicians use it in their evaluation of hyponatremia as it is in many standard diagnostic algorithms. However, the main question that urine osmolality answers is whether the hyponatremia is due to primary polydispsia, "beer potomania," or reset osmostat, which are rarely encountered by hospitalists as causes of hyponatremia.

The more typical diagnostic challenge is in distinguishing between hypovolemic hyponatremia and euvolemic hyponatremia (SIADH). Both hypovolemic hyponatremia and SIADH have elevated ADH levels, so they will have high urine osmolality. Therefore, FENa is the more useful test in helping to distinguish between hypovolemic hyponatremia and SIADH, as it provides information about the patient’s intravascular volume status. Determining the patient’s volume status is a key clinical decision point in determining whether a patient’s hyponatremia is from hypovolemia or SIADH.

Another reason that the urine osmolality is often unnecessary is that the specific gravity, which can be obtained from a urine dipstick, corresponds fairly well to the urine osmolality. A urine specific gravity of 1.001 corresponds roughly to a urine osmolality of 40 mOsmol/kg, while a urine specific gravity of 1.010 corresponds roughly to a urine osmolality of 320 mOsmol/kg, and a urine specific gravity of 1.030 corresponds roughly to a urine osmolality of 1200 mOsmol/kg. Specific gravity, unlike osmolality, is affected by urine particle size, so it can give skewed results when large particles, such as radiocontrast, are excreted into the urine.

Evaluation of Polyuria

One situation in which the urine osmolality is useful is in evaluating polyuria. It is important to determine early whether the polyuria is from a water diuresis or a solute diuresis. A urine osmolality less than 150 mOsm/kg suggests a water diuresis, whereas a urine osmolality greater than 300 mOsm/kg suggests a solute diuresis. Causes of a water diuresis include diabetes insipidus and excessive water intake, while causes of a solute diuresis include glucosuria and high salt intake.

III. Management while the Diagnostic Process is Proceeding

A. Management of the Clinical Problem.

Not applicable.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Eknoyan, G, Hostetter, T, Bakris, GL. "Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK)". American Journal of Kidney Diseases.
vol. 42. 2003. pp. 617-622.